Phosphodiesterases are enzymes that catalyse the hydrolysis of cyclic AMP and/or cyclic GMP in cells to 5-AMP and 5-GMP, respectively, and as such they are critical to cellular regulation of cAMP or cGMP levels. Of the 11 phosphodiesterases identified so far, phosphodiesterase (PDE) 4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important modulator of cAMP expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (Z. Huang and J. A. Mancini, Current Med. Chem. 13, 2006, pp. 3253-3262). As cAMP is a key second messenger in the modulation of inflammatory responses, PDE4 has been found to regulate inflammatory responses of inflammatory cells by modulating proinflammatory cytokines such as TNFα, IL-2, IFN-γ, GM-CSF and LTB4. Inhibition of PDE4 has therefore become an attractive target for the therapy of inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, Crohn's disease etc. (M. D. Houslay et al., Drug Discovery Today 10 (22), 2005, pp. 1503-1519; N. Press & K. H. Banner, Progress in Medicinal Chemistry 47, 2009, pp. 37-74). As atopic dermatitis (AD) patients have increased PDE-activity, PDE4-inhibition would also appear to be a viable treatment of AD (Journal of Investigative Dermatology (1986), 87(3), 372-6; N. Ishii et al., J. Pharmacol. Exper. Ter. 346, 2013, pp. 105-112).
The PDE4 gene family consists at least of four genes, A, B, C and D, which have a high degree of homology (V. Boswell Smith and D. Spina, Curr. Opinion Investig. Drugs 6(11), 2006, pp. 1136-1141). The four PDE4 isoforms are differentially expressed in different tissues and cell types. Thus, PDE4B is predominantly expressed in monocytes and neutrophils, but not in cortex and epithelial cells, while PDE4D is expressed in lung, cortex, cerebellum and T-cells (C. Kroegel and M. Foerster, Exp. Opinion Investig. Drugs 16(1), 2007, pp. 109-124).
Numerous PDE4 inhibitors have been studied for their therapeutic effect on inflammatory diseases, primarily asthma, inflammatory bowel disease and COPD. The first of these, theophylline, is a weak, non-selective phosphodiesterase inhibitor used in the treatment of respiratory diseases such as asthma and COPD. Treatment with theophylline may, however, give rise to both mild and severe adverse effects, e.g. arrhythmia and convulsions, restricting the clinical utility of theophylline (Kroegel and Foerster, supra). As phosphodiesterase 4 has remained an attractive target for anti-inflammatory therapy, several other, more selective PDE4 inhibitors have been developed and investigated in a clinical setting. The clinical development of many of the first-generation PDE4 inhibitors such as rolipram was discontinued due to dose-limiting side effects, primarily nausea and emesis. Second-generation PDE4 inhibitors with apparently less pronounced adverse effects are currently in clinical trials (Houslay, supra).
Compounds that exhibit PDE4 inhibitory activity have been proposed as therapeutic agents for systemic treatment of inflammatory allergic diseases such as bronchial asthma, COPD, allergic rhinitis, and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, and systemic lupus erythematosus; diseases of the central nervous system such as depression, amnesia, and dementia; organopathy associated with ischemic reflux caused by cardiac failure, shock, and cerebrovascular diseases, and the like; insulin-resistant diabetes; wounds; and other diseases where inflammation plays a part in the etiology or progression of the disease.
Compounds that exhibit PDE4 inhibitory activity may also be beneficial in preventing, treating or ameliorating a variety of dermal diseases or conditions, such as proliferative and inflammatory skin disorders and in particular psoriasis, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus, and eczema.
One of the pathogenic processes underlying the development of psoriasis is infiltration of the skin by activated immune cells, such as Th1 and Th17 cells, expressing cytokines that induce a self-perpetuating inflammatory cycle in psoriasis plaques. In particular, the cytokines TNFα, IL-17 and IL-22 have been shown to be of pivotal importance to the onset and progression of psoriasis. An in vitro assay using human peripheral blood T-cells that have been activated and differentiated to the Th1/Th17 phenotype was developed to assess the anti-inflammatory effect of test compounds by measuring their effect on cytokine expression.
In the course of research leading to the present invention, it was surprisingly found that when PDE4 inhibitors were tested in the Th1/Th17 assay, they upregulate the expression of the proinflammatory cytokine IL-22 and, to a lesser extent, IL-17. The expression of IL-22 is highly upregulated in patients with psoriasis and atopic dermatitis, stressing its role in chronic skin inflammatory conditions. Through its receptor which is expressed by cells of non-hemapoietic origin, such as epithelial cells including keratinocytes, endothelial cells and fibroblasts, IL-22 plays an important role in the induction of altered proliferation and differentiation of keratinocytes and for the expression of inflammatory molecules such as MCH class I, IL-6 and IL-8, thus promoting skin inflammation. The unexpected upregulation of a proinflammatory cytokine by compounds that have therapeutic potential as anti-inflammatory drugs provides a rationale for concurrent treatment with another therapeutically active compound capable of downregulating the expression of IL-22.